It has been revealed that when a blood vessel is injured, and the blood is in contact with the injured vascular wall or the subcutaneous tissue in the blood vessel or the tissue factor flows into the blood, the blood coagulation reaction is started in which fibrinogen in the blood is converted to insoluble fibrin, and a net of the fibrin functions as a strong haemostatic plug and hardens the wound.
It has been suggested from the past that blood coagulation is closely related to cancer (described in “Edema Caused by Thrombi in Limbs of Patient with Gastric Cancer” by a French surgeon Trousseau in the 1800s). Recent clinical epidemiologic data have revealed that the incidence of thrombosis due to hypercoagulation is significantly higher inpatients with most types of cancer including pancreatic cancer, gastric cancer, and brain tumors than in healthy people (NPL 1). It is thought that insoluble fibrin accumulation, coagulation necrosis, and angiogenesis due to abnormal coagulation occur repeatedly in cancer tissues with the progression of the cancer.
Insoluble fibrin is not present in tissues under normal physiological conditions in contrast to its precursor, fibrinogen, which is widely found in a living body. Fibrinogen is cleaved by thrombin which has leaked out from the blood vessel and which has been activated, and forms fibrin monomers. Then, the fibrin monomers are polymerized and cross-linked to form fibrin fiber. In this manner, insoluble fibrin is formed. For this reason, the insoluble fibrin is present specifically in tissues under a pathological condition such as hemorrhage or inflammation, and is formed at the occurrence of a pathological condition involving coagulation, such as cancer, myocardial infarction, or cerebral infarction. Accordingly, insoluble fibrin is a marker molecule of such thrombus-related diseases, and it can be truly said that insoluble fibrin present in a cancer tissue is a cancer-specific molecule especially under a situation where any cerebral or cardiovascular disease such as myocardial infarction or cerebral infarction is not present. As described above, insoluble fibrin is shown to be related with the thrombus formation and important diseases, and hence there is a demand for development of means for specifically detecting fibrin.
In view of such a situation, antibodies have been developed as means for detecting fibrin (PTLs 1 to 6). In addition, the present inventors have also developed an antibody which binds to fibrin and which does not bind to fibrinogen, and clarified the usefulness of the antibody (PTL 7).
However, since insoluble fibrin is formed when terminal portions are cleaved from the precursor, fibrinogen, the amino acid sequences of insoluble fibrin and fibrinogen are completely the same except for the presence or absence of the parts removed by the cleavage. Moreover, soluble fibrin (FDPs, fibrin degradation products) formed by degradation of insoluble fibrin with plasmin or the like may be present in a living organism in some cases. Accordingly, detection of insoluble fibrin in the presence of molecules (fibrinogen, FDPs, and the like) having extremely high homologies in terms of the amino acid sequence and the structure requires an antibody having a higher affinity for and a higher specificity to insoluble fibrin.